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Lenalidomide Inhibits Osteoclastogenesis, Survival Factors and Bone-Remodeling Markers in Multiple Myeloma

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Lenalidomide Inhibits Osteoclastogenesis, Survival Factors and Bone-Remodeling Markers in Multiple Myeloma Leukemia (2008) 22, 1925–1932 & 2008 Macmillan Publishers Limited All rights reserved 0887-6924/08 $32.00 www.nature.com/leu ORIGINAL ARTICLE Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma I Breitkreutz1, MS Raab1, S Vallet1, T Hideshima1, N Raje1, C Mitsiades1, D Chauhan1, Y Okawa1, NC Munshi1, PG Richardson1 and KC Anderson1 1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Osteolytic bone disease in multiple myeloma (MM) is caused by survival of 28 months and a median progression-free survival of enhanced osteoclast (OCL) activation and inhibition of osteo- 7.7 months.2 In two large-phase III studies comparing lenalido- blast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed mide/dexamethasone versus dexamethasone in relapsed MM, MM, and bortezomib has recently been reported to inhibit OCLs. extent and frequency of response, as well as progress free and We here investigated the effect of lenalidomide on OCL overall survival, were prolonged in the combined therapy formation and osteoclastogenesis in comparison with bortezo- cohort.3,4 The proteasome inhibitor bortezomib has potent mib. Both drugs decreased aVb3-integrin, tartrate-resistant acid anti-MM activity with impressive clinical responses, prolonging phosphatase-positive cells and bone resorption on dentin time to progression and overall survival in patients with relapsed disks. In addition, both agents decreased receptor activator of 5,6 nuclear factor-jB ligand (RANKL) secretion of bone marrow or refractory MM. In spite of these novel agents, osteolytic stromal cells (BMSCs) derived from MM patients. We identified bone disease remains a major source of morbidity, occurring in PU.1 and pERK as major targets of lenalidomide, and nuclear 70–80% of MM patients and associated with severe bone pain, factor of activated T cells of bortezomib, resulting in inhibition pathologic fractures, paralysis through nerve compression, of osteoclastogenesis. Furthermore, downregulation of cathe- hypercalcemia and death.7 Bisphosphonates inhibit osteoclast psin K, essential for resorption of the bone collagen matrix, was (OCL) activity and have been successfully and widely used for observed. We demonstrated a significant decrease of growth 8 and survival factors including macrophage inflammatory the treatment of MM bone disease; however, complications protein-a, B-cell activating factor and a proliferation-inducing induced by bisphosphonates can occur including osteonecrosis ligand. Importantly, in serum from MM patients treated with of the jaw, and their use is not recommended over a long period lenalidomide, the essential bone-remodeling factor RANKL, as of time. well as the RANKL/OPG ratio, were significantly reduced, Osteolytic lesions are primarily due to a dysregulation of the whereas osteoprotegerin (OPG) was increased. We conclude normal bone-remodeling process, with a decrease of osteoblast that both agents specifically target key factors in osteoclasto- genesis, and could directly affect the MM-OCL-BMSCs activa- (OBL) function accompanied by increased activation of OCLs. tion loop in osteolytic bone disease. In MM, this destructive bone process is enhanced by interaction Leukemia (2008) 22, 1925–1932; doi:10.1038/leu.2008.174; of MM cells with OCLs in the bone marrow (BM) microenviron- published online 3 July 2008 ment. Specifically, adhesion of MM cells to bone marrow Keywords: multiple myeloma; osteoclastogenesis; bone disease; stromal cells (BMSCs) induces secretion of osteolytic factors lenalidomide; bortezomib such as interleukin-6 (IL-6) and receptor activator of NF-kB ligand (RANKL), a tumor necrosis factor (TNF) family cytokine. IL-3 production stimulates osteoclastogenesis directly and enhances the effect of RANKL and of macrophage inflammatory Introduction protein-a (MIP-1a), an important growth and survival factor for MM cells and OCL.9 In addition, MM cells in the BM produce Multiple myeloma (MM) is a currently incurable malignant Dickkopf homologue 1, thereby inhibiting OBL activation by plasma cell disorder affecting approximately 15 000 new blocking Wnt signaling.10 patients in the United States annually. Novel drugs targeting Clinical observations revealed that bortezomib may trigger MM and its microenvironment have shown promising clinical OBL activation, evidenced by increased alkaline phosphatase in results.1 Thalidomide and its more potent immunodmodulatory the serum of MM patients responding to bortezomib treat- analog (IMiDs) lenalidomide have been successfully used in ment.11 Moreover, treatment with bortezomib in patients with MM treatment. Specifically, the results of a multicenter, open- relapsed MM significantly decreased RANKL and C-terminal labeled, randomized phase 2 study evaluating two dose cross-linking telopeptide of collagen type I (CTX).12 Recently, regimens of lenalidomide for relapsed, refractory myeloma von Metzler et al.13 showed that bortezomib inhibits osteoclas- show an overall response rate of lenalidomide alone of 25%. It togenesis by downregulation of p38 mitogen-activated protein was well tolerated at 30 mg once daily, with a median overall kinase (MAPK) and AP1. To date, however, the effect of lenalidomide on OCLs remains unknown. Furthermore, it is Correspondence: Dr KC Anderson or Dr I Breitkreutz, Department of not clear whether there is an inhibitory effect of lenalidomide or Medical Oncology, LeBow Institute for Myeloma Therapeutics, Jerome bortezomib on growth and survival factors that trigger Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, osteoclastogenesis and OCL activation. In this study, we Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. investigated whether lenalidomide, similar to bortezomib, E-mails: [email protected] or Iris_Breitkreutz@ dfci.harvard.edu affects activation and function of OCLs in the BM micro- Received 28 February 2008; revised 27 May 2008; accepted 30 May environment, osteoclastogenesis and related growths factors, as 2008; published online 3 July 2008 well as markers of bone turnover in MM. Lenalidomide, bortezomib inhibit osteoclasts in MM I Breitkreutz et al 1926 Materials and methods ELISA Cytokine secretion in supernatants from OCL cultures was Osteoclast formation assay measured using enzyme-linked immunosorbent assay (ELISA). OCLs were generated in vitro using peripheral blood mono- Specifically, OCLs were cultured in 96-well plates for 2 weeks; nuclear cells (PBMCs) from MM patients. Written informed supernatants were harvested, and MIP-1a, IL-6, B-cell activa- consent was obtained according to the Declaration of Helsinki. ting factor (BAFF) and a proliferation-inducing ligand (APRIL) For OCL formation assays, PBMCs were separated by secretion were measured using DuoSet ELISA development kits Ficoll-Paque gradient, and nonadherent cells were cultured in (R&D Systems Inc.) and Bender MedSystems (Burlingame, CA, 6- or 96-well plates (0.5 Â 06 cells per cm2), as previously USA), in accordance with manufacturer’s instructions. To described.14 OCLs were generated by culturing cells for 14–21 measure RANKL secretion, BMSCs were cultured in RPMI/ days in a-minimal essential medium containing 10% 20% FBS in the presence of lenalidomide or bortezomib. After fetal bovine serum (FBS), 1% penicillin-streptomycin (Media- 72 h, supernatant was harvested and subjected to RANKL ELISA tech Inc., Herndon, VA, USA), as well as 25 ng/ml of (Bender MedSystems Burlingame). macrophage colony-stimulating factor (M-CSF) (R&D Systems, Minneapolis, MN, USA) and RANKL (50 ng/ml) (PeproTech, Rocky Hill, NJ, USA). Western blot analysis PBMCs were cultured with RANKL (50 ng/ml) and M-CSF (25 ng/ ml) in the presence or absence of lenalidomide or bortezomib. Bone marrow stromal cell cultures PBMCs were seeded in six-well plates. Cells were harvested at BMSCs derived from MM patients were cultured in RPMI and specific time points with cell dissociation buffer (Invitrogen) and 20% FBS after separation of mononuclear cells via Ficoll-Paque M 4 lyzed in lysis buffer (50 m HEPES (N-2-hydroxyethylpipera- gradient. BMSCs were cultured in 96-well plates (0.5 Â 10 cells 0 M 2 zine-N 2-ethanesulfonic acid), pH 7.4, 150 m NaCl, 1% per cm ). Medium was changed twice weekly. Lenalidomide NP-40, 30 mM sodium pyrophosphate, 5 mM ethylenediamine- and bortezomib were diluted in culture medium and added to tetraacetic acid, 2 mM Na3VO4, 5 mM NaF, 1 mM phenylmethyl 1 BMSCs for 72 h. Supernatant was collected and stored at –80 C. sulfonyl fluoride, 5 mg/ml leupeptin and 5 mg/ml aprotinin). Total protein lysates were then subjected to sodium dodecyl sulfate– polyacrylamide gel electrophoresis, transferred to nitrocellulose Osteoclast differentiation and bone resorption assay membrane and immunoblotted with antibodies against pERK, After 2 weeks of incubation, OCLs in control and treated groups nuclear factor of activated T cells (NFATe1), c-fos (Santa Cruz were fixed with citrate-acetone solution and stained for tartrate- Biotechnology, Santa Cruz, CA, USA), as well as PU.1 and resistant acid phosphatase (TRAP) using an acid phosphatase cathepsin K (Cell Signaling Technology, Beverly, MA, USA). leukocyte staining kit (Sigma Chemical, Saint Louis, MO, USA). Antigen–antibody complexes were detected by enhanced TRAP-positive multinucleated OCLs containing
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